N-oxides of 1 -nitro-9-dialkylaminoalkylamino/acridine

ABSTRACT

The N-oxides of 1-nitro-9-(dialkylaminoalkylamino)acridine which are antitumor agents are produced by oxidizing the corresponding N10 or N oxides.

United States Patent 91 Ledocliowski et al.

1 N-OXIDES OF 1 -NITRO-9-DIALKYLAMINOALK- YLAMINO/ACRIDINE [75] Inventors: Andrzej Ledochowski, Gdansk;

Barbara Stefanska, Gdansk-Oliwa, both of Poland [73} Assignee: Starogadzkie Zaklady Farmaceutyczne Polfa, Starogard Gdanski, Poland 22 Filed: Oct. 4, 1973 21 Appl. No.: 403,624

Related US. Application Data [60] Continuation of Ser. No. 201,945, Nov. 24, 1971, abandoned, which is a division of Ser. No. 854,608,

Sept. 2, 1969, Pat. No. 3,694,448.

[30] Foreign Application Priority Data Aug. 31, 1968 Poland P128855 [451 July 29,1975

[52] US. Cl 260/279 A [51] Int. Cl C07d 37/24 [58] Field of Search 260/279 R. 279 A [56] References Cited UNITED STATES PATENTS 2,500,131 3/1950 Linsker 260/279 A FOREIGN PATENTS OR APPLICATIONS 1,093,847 12/1967 United Kingdom 260/279 A Primary Examiner-Donald G. Daus Assistant Examiner-Mary C. Vaughn Attorney, Agent, or Firm-Waters, Schwartz & Nissen [57] ABSTRACT The N-oxides of 1-nitr0-9-(dialkylaminoalkylamino)acridine which are antitumor agents are produced by oxidizing the corresponding N or N oxides.

2 Claims, No Drawings N-OXIDES OF 1 -NITRO-9-DIALKYLAMINOALKYLAMINO/ACRI- DINE CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation application of Ser. No. 201,945, filed Nov. 24, 1971 now abandoned which in turn is a division of Ser. No. 854,608, filed Sept. 2, 1969 and issued as US. Pat. No. 3,694,448 on Sept. 26, 1972.

BACKGROUND OF THE INVENTION The invention relates to novel acridine derivatives useful as antitumor agents and methods for their production.

DETAILED DESCRIPTION The present invention is directed to new acridine derivatives, viz., the N-oxides of l-nitro-9-(dialk ylaminoalkylamino)acridine of the general formula:

wherein R is a straight or branched chain lower alkylene group and R is a lower alkyl group, where the oxygen atoms may be added simultaneously to the nitrogen atoms in both the N or N positions or to only one of said nitrogen atoms.

R, may for instance be methylene, ethylene, propylene or butylene. Preferably it is propylene. R may for instance be methyl, ethyl or propyl and preferably is methyl.

These derivatives constitute a group of compounds exhibiting strong biological activity, in particular antitumor activity. As can be seen from the prior literature, these compounds were heretofore unknown and consequently the discovery of their antitumor properties is quite new.

For instance, the novel N" -oxide, of l-nitro-9-(3- dimethylaminopropylamino) acridine, tested by means of the methods described below, and which are used for obtaining preliminary preclinical estimates of the value of new compounds, exhibits the following antitumor activity:

In vitro tests:

On growing a KB line tumorous tissue (human tumor), the above compound inhibits by 50% the albumin increase (L so) at a concentration of l0 g/ml.

In the Miysmura test the said compound shows a very strong activitythe inhibition zone of the dehydrgenase activity of Ehrlich carcinoma cells amounts to 22 mm at a concentration of 1 mg/ml.

In vivo tests:

The growth of a Crocker 180 mouse sarcoma is in hibited by said compound by up to 4060% when using doses of 2-4 mg/kg.

no oxygen atoms added to the nitrogen atoms in position N and/or N According to the invention, l-nitro-9- (dialkylaminoalkylamino)acridine N -oxides are obtained by causing an oxidizing agent, preferably perbenzoic acid or perphthalic acid, in an organic solvent medium such as chloroform, etc., at a temperature of 30C, to act upon l-nitro-9-(dialkylaminoalkylamino)acridine.

Likewise according to the above method, by acting with the oxidizing agent at 5C, N-oxides of l-nitro- 9(dialkylaminoalkylamino)acridine are converted to N N -dioxides of 1-nitro-9-(dialkylaminoalkylamino)acridine. On the other hand, l-nitro-9-(dialkylaminoalkylamino)acridine N-oxides according to the invention are obtainable by heating the N-oxides of l'nitroacridine derivatives, having in the 9 position a chlorine atom, a phenoxy group of an alkoxy group, with a dialkylaminoalkylamino or the hydrochloride thereof, in a phenolic medium, at a temperature of l20C for 30-120 minutes.

It is also possible to use in the above condensation, the adduct of l-nitro-9-chloroacridine N-oxide with pyridine. For this purpose, lnitro-9-chloroacridine N- oxide is heated with pyridine at the boiling point of pyridine or at a lower temperature, then the mixture is cooled and by adding ether, the pyridine adduct of 1-nitro-9-chloroacridine N-oxide is precipitated.

The starting l-nitro-9-chloro-, phenoxyor alkoxyacridine N-oxides according to the present invention are obtained by causing an oxidizing agent, preferably perbenzoic or perphthalic acid, in an organic solvent medium such as chloroform, to act upon 1-nitro-9-chloro-, phenoxyor alkoxyacridine. It is also possible to obtain the required l-nitro-9-phenoxyacridine N-oxide from l-nitro-9-chloroacridine N-oxide by treating same with phenol or sodium phenolate at a temperature of 80l20C for 30l20 minutes.

EXAMPLE I To a chloroform solution of 1.6g of l-nitro-9-(3- dimethylaminopropylamino)-acridine is added, at a temperature of 35C, a chloroform solution of 0.8 g of parbenzoic acid, whereupon the mixture is left for 18 hours at room temperature. Then the dihydrochloride of the N -oxide of l-nitro-9-(3'-dimethylaminopropylamino)-acridine is precipitated by adding an ether solution of hydrogen chloride thereto. Melting point 196C, yield EXAMPLE II To a chloroform solution of 1.65 g of 1-nitro-9-(4'- dimethylaminobutylamino)-acridine is added, at a temperature of 35C, a chloroform solution of 0.8 g of perbenzoic acid and the mixture is left for 18 hours at room temperature. The addition of an ether solution of hydrogen chloride causes precipitation of the dihydrochloride of l-nitro-9-(4- dimethylaminobutylamino)acridine N -oxide having a melting point of 178C with decomposition in a yield of 60%.

EXAMPLE 111 To a chloroform solution of 1.7 g of 1'-nitro-9-(3'- dimethylaminopropylamino)-acridine N cooled to a temperature of 5C, a chloroform solution of 0.8 g of perbenzoic acid is added and the mixture is then left for 5 hours at a temperature of 5C. The addition of an ether solution of hydrogen chloride causes precipitation of l-nitro-9-(3'-dimethylaminopropy1amino)- acridine di N" N -oxide dihydrochloride, having a melting point of 212C with decomposition in a yield of 45%.

EXAMPLE IV 2.6 g of l-nitro-9-chloroacridine are dissolved in 10 ml of chloroform and after adding 1.6 g of perbenzoic acid in 30 ml of chloroform, the mixture is left for hours at room temperature, whereupon the solvent is distilled off in the presence of a platinum foil under reduced pressure. From the residue, by means of the addition of ether, a deposit is precipitated which is then subjected to crystallization from a benzenecyclohexane mixture. 2.3 g of 1-nitro-9-chloroacridine N -oxide with a melting point of l72-l73C are obtained.

EXAMPLE V 2.8 g of l-nitro-9-chloroacridine N -oxide for half an hour at a temperature of 8090C with 1.3 g of sodium phenolate in 10 g of phenol. After cooling and pouring and mixture into a 2N sodium hydroxide solution, l-nitro-9-phenoxyacridine N -oxide having a melting point of 207C in a yield of 85% is obtained.

EXAMPLE V1 0.3 g of 1-nitro-9-chl0roacridine N -oxide is heated for 1 hour at a temperature of 120C with 3 g of phenol. After isolation, as in Example V, 1-nitro-9- phenoxyacridine N -oxide in a yield of 70% is obtained.

EXAMPLE V11 To a chloroform solution of 3.1 g of l-nitro-9 phenoxyacridine, a chloroform solution of 1.6 g of perbenzoic acid is added and the mixture is left for 24 hours at room temperature. The chloroform solution is then washed with a 10% aqueous potassium carbonate solution and thereafter with water, whereupon it is dried and the chloroform is distilled off in the presence of a platinum foil under reduced pressure. The obtained deposit is purified by crystallization from a benzene-cyclohexane mixture. 1-nitro-9-phenoxyacridine N' -oxide having a melting point of 207C is obtained.

EXAMPLE V1" 1.4 g of l-nitro-9chloroacridine N-oxide are heated with 10 ml of pyridine for half an hour at a temperature of 80C, whereupon, by means of ether, a deposit is precipitated which is washed with hot benzene. After crystallization from a methanol/ether mixture, at pyridine adduct of 1-nitro-9-chloroacridine N -oxide having a melting point of 210C in a yield of is obtained.

EXAMPLE 1X 28 grams of 1-nitro-9-chlor0acridine N-oxide are heated for 1 hour at a temperature of 120C with 10 g of phenol, whereupon after 1.5 ml of dimethylaminopropylamine have been added, the mixture is kept for half an hour at a temperature of C. After cooling and pouring the mixture into an ether solution of hydrogen chloride. l-nitro-9-(3-dimethylaminopropylamino)-acridine N-oxide dihydrochloride having a melting point of 230C with decomposition, in a yield of 55 is obtained.

EXAMPLE X 1.65 g of 9-phenoxyacridine N-oxide and 0.75 ml of dimethylaminopropylamine are heated for 40 minutes at a temperature of 90100C with 8 g of phenol. After cooling and isolation as in Example 1X, l-nitro-9-(3'- dimethylaminopropylamino)acridine N -oxide dihydrochloride in a yield of 65% is obtained.

EXAMPLE XI wherein R is a straight or branched chain alkylene group having 1 to 4 carbon atoms and R is a lower alkyl group having 1 to 3 carbon atoms: and pharmaceutically acceptable acid addition salts of said compound.

2. A compound as claimed in claim 1 which is l- Nitro-9-(3-dimethylaminopropylamino)-acridine N N -dioxide, and the dihydrochloride thereof. 

1. A COMPOUND OF THE FORMULA
 2. A compound as claimed in claim 1 which is 1-Nitro-9-(3''-dimethylaminopropylamino)-acridine N10, N -dioxide, and the dihydrochloride thereof. 